Human herpesvirus 6, HHV-6, exists in at least two strain groups: variant A and variant B, HHV-6A and HHV-6B. They are closely related, averaging 5% in herpesvirus conserved genes with greater divergence at the ends of the genomes and selected sites between conserved gene blocks (1-3). These variants are related to a smaller genome of human herpesvirus 7 (HHV-7) forming the Roseoloviruses and together with the more distant human cytomegalovirus form the betaherpesvirus subgroup of the herpesvirus family, maintaining a conserved gene order and similarity in sites of latency including monocytic/macrophage cell types. HHV-6A and HHV-6B have differing geographic prevalence with HHV-6B dominant in USA, Europe and Japan, while HHV-6A appears only a minor variant except in African countries where it appears equally prevalent to HHV-6B (4, 5). However exhaustive surveys have not been conducted using serological specific reagents given the close relation between these viruses. There are hotspots for variation between representatives of these virus genomes and these may contribute to some cellular tropism and pathological differences which have been anecdotally reported. For example, only HHV-6A has been detected in skin biopsies and HHV-6A has been increasingly implicated in cases of multiple sclerosis where careful genotyping and identification of active infections have been carried out (5-10). These studies either implicate immune abnormalities in clearance of the virus or possible complications of rare primary adult infection with this variant, since in countries where this has been studied HHV-6B is the predominant variant identified.
Both HHV-6A and HHV-6B have cellular tropisms for CD4+ T-lymphocytes, and both are neurotropic, although there may be differences in the exact site of latency given the more disperse detection of HHV-6A where studies have been undertaken. Interestingly, the chemokine encoded by HHV-6 is highly divergent between these strain variant groups and thus would be a major candidate for determining pathogenic differences.
Chemokines are main mediators of an inflammatory response and can control chemotaxis of leukocyte populations to an infectious centre. In HCMV, for example, the UL146 chemokine is specific for alpha chemokines and can control dissemination of the virus in specifically chemoattracted neutrophils. There is another locus encoding an HCMV chemokine, UL126, and this also appears to affect cellular tropism, in that passage in fibroblasts results in deletion or alteration to this gene (11-13). This gene has similarities to betachemokines which can chemoattract monocytes and a similar function in murine CMV, vMCK, has been shown essential for virus dissemination (14-16). In HHV-6, there is a single chemokine gene, which is deleted in HHV-7, the highly variable U83. In HHV-6B this molecule (referred to as U83B) has been characterised as an efficient selective CCR2 agonist although with low potency (17). Earlier studies have shown chemotactic activity for monocytic THP-1 cells which express this receptor (18) and are consistent with the role of monocytic cells as sites for latent infection.
The published sequence of the U83 gene from HHV-6A, U83A, includes a signal sequence predicted not to permit secretion of the gene product. As a consequence, the U83A gene product is believed unlikely to have any chemokine-like properties.
The present inventors have surprisingly identified that the U83A sequence is polymorphic, with a novel sequence described herein having a functional secretory signal sequence. The present inventors have also identified that the secreted peptide has agonistic and antagonistic properties against a remarkably wide range of chemokine receptors. The U83A product is also produced in a short splice variant, U83A-Npep, which displays antagonistic properties against a range of chemokine receptors.